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Wednesday, November 07, 2007

Clinical Trial Results Lost in the MIST

We have been preoccupied on this side of the pond with the release of lists of more than a thousand orthopedic surgeons who received payments, often huge, from manufacturers of joint prostheses (see posts here, here, and here). Meanwhile, another important story involving medical devices has surfaced.

A detailed version was reported by TheHeart.org, and summarized by Dr Aubrey Blumsohn on the Scientific Misconduct Blog. So I will just try to do a shorter summary that does it justice. (Quotes are from TheHeart.org unless otherwise indicated.)

The Migraine Intervention with STARflex Technology (MIST) trial was meant to determine if closing a patent foramen ovale (PTO), a defect in the wall separating two heart chambers, would reduce migraine headaches. This study question was based on the finding that patients who had their PTOs closed after a stroke had fewer migraines. Initially, the trial had two principal investigators, Dr Peter Wilmshurst, "cardiology principal investigator," a noted British cardiologist, and Dr Andrew Dowson, "lead headache specialist," who is "not in fact a neurologist," and who has "'undertakings,' or restrictions [on his practice] relating to past research misconduct." The trial was sponsored by NMT Medical, the manufacturer of STARflex.

The trial failed to show any advantage due to PTO closure. One theory raised to explain this was that patients often still had shunt flow across heart chambers after the procedure. Dr Wilmshurst was sent all patients' echocardiograms for independent review. Wilmshurst did find a high rate, about one-third, of patients had residual shunt flow. Wilmshurst said a second review by Dr Luke Missault produced similar results.

According to TheHeart.org, " while a higher rate of residual shunts would help explain the negative outcome in MIST, it has much larger implications for a device already marketed in Europe for the treatment of cryptogenic stroke."

After Wilmshurst found this high rate of residual shunt flow, he claims he was prevented from revieiwing the trial's data set. "Wilmshurst and colleagues at Shrewsbury, including Dr Simon Nightingale, who is also on the MIST steering committee, have also repeatedly asked for the complete line data collected in the MIST trial. According to Wilmshurst, the data they have seen, most of it already analyzed and compiled by the clinical research organization (CRO), are simply inconsistent with what they themselves saw at their own clinic. They were given access to some of the line data, but never the complete data set, he told heartwire."

In fact, "Wilmshurst states that all communications with NMT ground to a halt after he told the company the results of his review of the residual shunts."

Since then, NMT has denied that Wilmshurst was ever a co-Principal Investigator for the trial. The company claimed that his hospital was dropped from further trials as a research center, but Wilmshurst claimed he was never informed of any protocol violations. When asked about these alleged protocol violations, [NMT vice president and chief financial officer Richard] "Davis replied, 'I won't get into that....'" Wilmshurst said that recently "the company has responded to his emails only by threatening him with legal action and telling hime he is forbidden to speak publicly about the trial.

Wilmshurst only found out that data from the MIST trial were going to be presented at the TCT 2007 meeting when he arrived there and saw the program. At the meeting, "Dowson reported that the closure success rate was 94%, according to the implanting physician - in other words, a residual shunt rate of 6% for the trial," sharply contradicting the results of Wilmshurst's review.Finally, Wilmshurst claims he has been cut out of the preparation of the first major article to come from the trial. "According to Dowson, the study has been accepted by Circulation, and he expects it to be published in a matter of weeks. Wilmshurst, who has been involved in the planning and execution of this trial from the outset, learned that the study had been accepted for publication only when he returned from the TCT; an email notifying him of its acceptance was sent to him while he was out of the office the previous week. He states that he never saw the final version of the paper before it was submitted, although he had initially contributed to its first draft-literature search, methods, discussion, etc-before the final results were in and had commented extensively on an earlier version of the paper. "

Note also that "Wilmshurst notes that he and Nightingale turned down 'large' consultancy payments from the sponsor; Dowson acknowledged during his TCT presentation that he has received funds from NMT, and Davis estimated that up to 10 investigators or steering committee members receive consulting fees from the company."

So let's see, in this case we have allegations that a medical device company that sponsored a research trial attempted to suppress a re-analysis of the data that showed its device in an unfavorable light; prevented a respected co-Principal Investigator from seeing all the trial data, and cut him out of the preparation of the key results paper; and tried to prevent him from talking about the trial in public.

Dr Aubrey Blumsohn commented, " In fact it seems hard to know whether this is science or black magic."

What is most troubling here to me?

Suppressing data about clinical trials that is unfavorable to a sponsor's product deprives patients and physicians of information that would have helped them make better decisions about health care.

In particular, suppressing data that suggests a device may not be as effective as previously thought means that some patients may undergo unnecessary, useless or even harmful procedures.

Suppressing data about clinical trials that is unfavorable to a sponsor's product violates the trust of the trial subjects who thought that the data their participation generated would go to advance science and improve medicine.

Finally, physicians and scientists who personally receive payments from sponsors may be less inclined to criticize these sponsors or their products

Again, this is a reminder about why we ought to reconsider whether to let those with vested interests in having clinical research come out a certain way control how this research is done.

1 comment:

Anonymous
said...

A new U.S. law (PL 110-85, Section 801) expands the registration requirements at ClinicalTrials.gov (e.g., mandatory registration of device trials, prospective disclosure of outcome measures) and mandates results reporting of clinical trials. The law also includes penalties for non-compliance.

As a result, it will likely be more difficult to suppress information about a clinical trial as well results data in the future. More information is available at http://prsinfo.clinicaltrials.gov/fdaaa.html

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